Dolichol deprivation theory

General Discussion
#81

Since this thread is getting pretty long, I’d like to re-summarize the science behind dolichol deprivation, the proposed treatment, and our results so far. 5 alpha reductase type 3 (SRD5A3) and its function was recently discovered, and it was also discovered only last year that finasteride inhibits SRD5A3 about the same as 5 alpha reductase type 2. SRD5A3’s primary function is to synthesize a special sort of alcohol called “dolichol” which is used in protein folding within the endoplasmic reticulum of cells for the very beginning stages of glycosylation. Glycosylation is an extremely important cellular process which is both upstream and the precursor to proper function of the higher functions of the body (including thyroid function, liver function, hormone function, and many more). Disruption of the glycosylation process can affect almost every system in the body, and can cause a cascade reaction causing a multitude of system-wide dysfunctions, including endocrinopathies (dysfunctional endocrine system), secondary hypogonadism, small testicles, muscle weakness, muscle atrophy, poor motor skills, stroke-like episodes (e.g. brain fog), cognitive impairment, speech difficulties, vitamin D deficiency, and many more.

Here is the abridged version of how most likely our syndrome is created (you can read earlier in this thread for a more detailed explanation complete with research sources): Finasteride inhibits 5 alpha reductase type 3 > Inhibited SRD5A3 inhibits dolichol production > Endoplasmic Reticulum becomes stressed due to incompetent protein folding due to dolichol deprivation > ER initiates the Unfolded Protein Response due to overwhelming stress caused by too many unfolded proteins > UPR causes upregulation of gene expressions associated in dolichol production (such as the GlcNAc-1-P transferase (GPT) gene) > overexpressed GPT gene hinders Lec35 gene product (Lec35p) > hindered Lec35p causes inefficient usage of dolichol (yet dolichol and Lec35p levels remain normal) > inefficient usage of dolichol stresses the ER and continues the loop > this causes a persistent disorder of glycosylation (aka psuedo-congenital disorder of glycosylation).

5 alpha reductase type 2 has been, for the longest time, the focal point of our research and understanding of PFS, but it isn’t until now that we can see the effects of inhibiting 5 alpha reductase type 3. Unlike what most other theories suggest, a glycosylation disorder would be our “root” cause, as it is upstream of basically every higher function in the body, including cortisol production, thyroid function, liver function, hormone function, and nearly everything else. Every other theory may address the cause of our symptoms, but what’s causing the cause? For example, we almost certainly get many of our symptoms due to a dysfunctional endocrine system, but what is causing our endocrine systems to be (and remain) dysfunctional? Why do treatments not correct the problem like they should? Why does TRT not solve our problem? Why do we have such a wide range of symptoms? Why can anti-biotics cause a positive change? Why can tyrosine cause a positive change? Why do we share many of the same symptoms as statin users? Why does caffeine and alcohol affect us? A glycosylation disorder, brought on by an altered gene expression, brought on by dolichol deprivation, caused by finasteride inhibiting SRD5A3 explains everything, and has a direct link through and through.

Based off of this data, a treatment was devised in the hopes of (theoretically) reversing the glycosylation disorder. Raw uncooked spinach is one of the few natural resources of dolichol, so a protocol of eating one 6oz bag of spinach a day for at least a month was created. So far, at least 2 of us have been responding very positively to the treatment (19 and myself), whereas others have yet to see a noticeable effect. Though the data is limited and still in the very early stages (only a couple of weeks since the beginning, and only a handful of volunteers so far), it may suggest that people who’ve taken finasteride for a short period of time tend to respond faster to this treatment, and people who’ve taken finasteride for a much longer period of time may respond more slowly. Additionally, ScaredinMD is looking into the (super expensive) Ropren medication, which is the only dolichol supplement currently available. It’s possible that a higher dose of dolichol through this medication may have a much greater effect than what a dolichol enriched diet could do. This is what we know so far, and it’s extremely exciting to potentially be on the verge of a breakthrough in both understanding our condition, as well as treating it.

#82

Tips for people trying this:

  • don’t overdo things - take time to relax
  • don’t eat too heavy foods and avoid chocolate, caffeine and refined sugars
  • don’t masturbate too often - once a week is ok - my body is very sensitive and i think this sort of burns too many resources

These things have set me back a bit.

Going to avoid this forum for a week. Be back then.

#83

Guys, I’ve fallen off the wagon. I did this thing until I was blue in the face and didn’t get results. Just lots of diarrhea, green poo, and I felt terrible. I’m going to keep watching this thread and if more of you get better, I’ll consider trying it again, but for now I’m going to need to see at least 2-3 full recoveries because eating that much spinach again.

#84

I tried this for about a week too. No improvements either. Maybe those of us who were on Fin for an extended period of time are beyond this treatment. Tryingnot only took a few doses vs. those of us who took hundreds of doses.

#85

Well I wouldn’t jump to the conclusion that you’re beyond this treatment, and it hasn’t even been a month yet. Once again, don’t base your results entirely on my timeline, it needs to be on your own. This isn’t some silver bullet that will instantly cure you, the point is to bring down the stress of the endoplasmic reticulum of your cells and convince them out of a dolichol-deprived panic mode. How much time and how much dolichol you’d need to suppliment is entirely up to your body’s needs. Ropren may be a good alternative to the spinach diet, but it’s ridiculously expensive at the moment.

#86

Unfortunately as with every theory, this concept needs to be tested for and proven in a lab.

Just a side note, I’ve eaten spinach before, while on and since being off Finasteride and it has made no difference in terms of improving my symptoms.

#87

It would be awesome if we could get a laboratory test for a glycosylation disorder. Unfortunately I personally don’t have the means to be able to do so, but I do think it would be worth looking into with the recent discovery of 5-alpha reductase type 3.

Also what kind of spinach were you eating (raw or cooked)? How much were you eating? How long were you eating it for?

#88

Know I said I’d stay away but been regressing a bit last few days.

I have started working out again though so maybe I’m putting too much stress on myself. Fatigue starting to set in again.

Something crossed my mind just now. I remember when I wrote an essay on human ageing and why it happens and what seems to prolong life. I talked about food deprivation and it was found that by starving just enough (in Drosophila) that they would actually live longer. However, this comes at the cost of reproduction. The idea is that when in a stressed situation the body sacrifices the reproductive function in order to maintain itself.

We are designed primarily for reproduction and normally our bodies are disposable hence our bodies age but our sperm don’t. Its called the disposable soma theory. They are set at day 1. However, when under stress like us we lose this in order to try and maintain ourselves. Normally things would get fixed and then reproductive function would come back. But maybe in us we are sort of trapped there. Food for thought.

#89

19
your food deprivation theory has a lot of weight. I used to fast for months, stopping eating from dawn to dusk and each time I did it ,got new life, more energy ,better digestive systems and much much more but with no weight loss or weakness. I was surprised how much human body is flexible but now I can not do this. I tried but got kind of hypoglycemic so had to stop it. I know modern science is against fasting but my personal experience is totally against it further Science is not conclusive abut many things it doesn’t say any thing against 5AR inhibitors.

sps

#90

I’m not saying we should be fasting. I’m saying when the body is stressed it can sacrifice functions.

#91

I will continue the spinach diet a little longer but not that optimistic about it now.

HOWEVER, I wanted to state the facts of this idea because I think the science is relevant and is worth pursuing. I might use some of the same references as tntw but wanted to gather it all here.

First of finasteride does affect SRD5a-3?

related.springerprotocols.com/lp/de-gruyter/human-type-3-5-reductase-is-expressed-in-peripheral-tissues-at-higher-HwVY3MbV0i

We found that highly sensitive to finasteride and dutasteride and shows similar sensitivity as SRD5a-2 for finasteride, while it is much more sensitive to dutasteride. The enzyme is highly expressed in the human skin, brain, mammary gland and breast cancer cells. Our data strongly suggest that SRD5a-3 could be the main enzyme responsible for 5areductase activity, previously believed to be associated with SRD5a-1, in many tissues and cell lines.

[b]Secondly what does SRD5a-3 do?

The enzyme efficiently catalyzes the transformation of T into DHT and has been reported to be highly expressed in the pancreas and refractory prostate cancers, (from above link).

researchgate.net/publication/5861012_Novel_5_alpha-steroid_reductase_%28SRD5A3_type-3%29_is_overexpressed_in_hormone-refractory_prostate_cancer

SRD5A3, is associated with DHT production and maintenance of androgen-androgen receptor-pathway activation in HRPC cells, and that this enzymatic activity should be a promising molecular target for prostate cancer therapy.

ncbi.nlm.nih.gov/pubmed/20637498

We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

cell.com/abstract/S0092-8674(1000772-5

The steroid 5α-reductase (SRD5A) family of enzymes produces steroid hormones that regulate male sexual development. Now, Cantagrel et al., 2010 identify a member of this family, SRD5A3, as a polyprenol reductase with a crucial role in N-linked protein glycosylation and pinpoint SRD5A3 mutations as the cause of a rare Mendelian disease.

cancerpreventionresearch.aacrjournals.org/cgi/content/short/3/12_MeetingAbstracts/A105?rss=1

We investigated how androgen regulates expression of isoenzymes of 5-reductase encoded by different genes—SRD5A1, SRD5A2, and SRD5A3—and in turn how finasteride may affect this regulation. By using different prostate cell lines, we found that androgen regulates the mRNA level of 5-reductase isoenzymes in a cell type-specific manner. This regulation, we demonstrated, requires AR and occurs at the transcriptional level. Moreover, we found that finasteride affects androgen regulation of 5-reductase expression in a cell type- and AR status-dependent manner. Finasteride counteracts testosterone-driven but not dihydrotestosterone-driven regulation of 5-reductase expression in LAPC-4 cells, which express wild type AR. However, finasteride does not affect testosterone or dihydrotestosterone regulation of 5-reductase expression in LNCaP cells, which express a mutant AR (T877A). Our findings suggest that dihydrotestosterone is the major regulator of 5-reductase expression and that finasteride may produce additional antitumor effects through other mechanisms besides inhibiting 5-reductase activity. The differential expression levels of 5-reductase isoenzymes may be one of the factors conferring response or resistance to finasteride treatment and thus may prove significant in prostate cancer prevention.

So whats dolichol about?

sciencedaily.com/releases/2010/07/100715142439.htm

The UCSD work revealed the molecular basis of an essential, but mysterious, enzymatic reaction in protein glycosylation. “We found the long-sought polyprenol reductase that has been suspected for decades” said Gleeson, a Howard Hughes Medical Institute Investigator who supervised the research. “Using a human genetic approach, we were able to not only find a clue to understand this class of disorder, but also to solve a basic science problem.” After translation, many proteins are modified with the addition of glycans (polysaccharides or oligosaccharides) that are necessary to help them perform their functions. This modification occurs in a specific cell compartment – the membrane of the endoplasmic reticulum – where the glycans are transported by a lipid before transferring onto proteins. Dolichol is the lipid carrier for glycans used during protein glycosylation; its availability is critical to accomplishing the modification process, but the synthesis or production of dolichol was poorly understood, especially the last step when polyprenol, a natural long-chain alcohol, is reduced to create dolichol. “Dolichol is used by the cell like a truck to transport glycans to their destination but also as a support to build them” said Vincent Cantagrel, a UC San Diego postdoctoral fellow and study co-author. “A defect in this transportation results in a less efficient process of glycosylation. Some proteins will miss some glycan chains and will not function correctly.”
In CDG cases, the conversion from polyprenol to dolichol is blocked by a mutation in the SRD5A3 gene.

“The key was identifying the enzyme’s role in producing dolichol. This is the basic step that is blocked in our patients, and the disease is the result. Our idea is that if you feed these patients dolichol, that might just treat the condition. It would be similar to giving insulin to diabetics. It’s a simple solution, but one nobody had thought of.”

I think this area also warrants investigation and there is enough evidence to back that up. Could it be part of the explanation of what is wrong with us? It is very possible. I hope scientists look into this and I ask Mew (if he can) to pass these references onto whoever could look into our problem.

#92

great info but how would you explain for some users who have normal or above normal DHT in blood? Maybe as Awor once said blood tests are not that conclusive.Unlike Testosterone DHT is local enzyme, means it produced where needed.

sps

#93

spstriken - A glycosylation disorder can cause a dysfunctional endocrine system. Hormones come into play further downstream of this cellular process, and it’s not as simple as why you would have more or less DHT. Hormone fluctuations and symptoms due to hormone fluctuations would only be symptoms themselves if our root cause is indeed a glycosylation disorder.

#94

Here’s an update with how I’m doing. It’s been about 3 weeks and two days since I started the spinach diet, and for the past few days things are slowly starting to get worse, but in a different way.

Before I started I was having problems with lack of energy, lack of emotions, testicle pain, lack of morning erections, low libido, ejaculate was extra thick and was a darker yellow than usual, my penis was numb and orgasm didn’t have any pleasurable feelings.

Things all improved back to 100% with the spinach diet, but after 3 weeks things seem to be starting to shift over into different symptoms. My energy is still fine and I’m feeling emotions quite well, but my motivation is starting to get worse. I’m getting morning erections every day now, but now I’m having more problems with erectile dysfunction for when I want to have them. My penis isn’t as numb and I’m not having testicle pain anymore, but it’s less warm and my ejaculate is starting to get very watery. My libido went back down, but not in the same way as before. It’s sort of hard to explain. Before I didn’t have the capacity to have sexual feelings, even though I desperately wanted to. Now I can have sexual feelings, but they don’t seem to be interesting anymore. For about 3 weeks during the spinach diet everything was awesome, but now it’s all starting to seem really boring. This probably stems from the same root as the lack of motivation problem.

So how does this fit into with what supplementing dolichol did? It’s strange that I had a set of problems before, was completely cured, and then came out the other side with a different set of problems. This would have to be studied in a lab to find out for sure, but if I had to theorize, I’d say it’s possible that by supplementing with exogenous dolichol, it may have downregulated my endogenous dolichol production. So now instead of having an overexpressed GPT gene, I may now have an underexpressed GPT gene. This could potentially be a very good thing, and weening off of spinach over the course of two weeks may allow things to properly balance out, and then break the cycle altogether. Another possibility could be iron overload from eating too much spinach, which also has its own set of problems. Either way, weening off of the spinach diet should be the next logical step for me. I’ll keep you guys updated.

#95

Sorry to hear that. Let us know how you get on.

Also i am doubting the idea of an acquired disorder of glycosylation. The symptoms don’t really add up. I looked at the table and I realised I have seen kids with these inherited conditions. They are very very ill. Way more so than us.

ncbi.nlm.nih.gov/books/NBK1939/

Also if 5 alpha reductase type 2 and 3 were not back online DHT levels would be low. Maybe they are out of balance but this would mean direct DHT supplementation would work. It doesn’t in the majority.

Having said that the fact finasteride inhibits 5 alpha reductase type 2 and 3 could help point to the problem and the suppressed dolichol may contribute to the persistent state. Perhaps by supplementing dolichol you inadvertently cause a change in the maintenance of the androgen androgen receptor pathway activation through an alteration in expression of SRD5a3.

Perhaps.

I will continue for another week or so with the spinach.

#96

Those who were born with a congenital disorder of glycosylation have several major differences between themselves and the PFS sufferers. First of all they inherited the condition, and their bodies were not only dysfunctional, but also developmentally stunted. However when our condition came about, we were completely developed and past puberty, so we do not share the same effects of being born with this. Just imagine how you would end up if you had PFS as a baby. Second, CDG sufferers have a permanent disorder that is preventing glycosylation, whereas we would merely have an imbalance that would otherwise work correctly. For example, we should still have a functional SRD5A3 enzyme, whereas CDG sufferers may not.

Here’s an article that elaborates on the conditions resulting in an acquired psuedo-CDG. It also explains how blood tests would not be able to identify it.

I think you’re confusing dolichol deprivation with another theory. 5 alpha reductase type 2 & 3 should indeed be online, as finasteride is no longer inhibiting it. Supplementing DHT doesn’t have anything to do with correcting a glycosylation disorder caused by the inefficient utilization of dolichol.

Finasteride is known to inhibit SRD5A3, inhibited SRD5A3 has been shown to inhibit dolichol, dolichol deprivation is known to induce the unfolded protein response, the unfolded protein response has been known to alter gene expressions, and over/underexpression of genes associated in dolichol utilization has been linked to psuedo-congenital disorders of glycosylation. The intention of adding more dolichol is to compensate for the body’s inefficient utilization of it. Do you have any sources to support your alternative theory?

I strongly suggest you ween off of it over the next two weeks. You would not want your cells to potentially induce another UPR.

I’m starting to notice a pattern emerging from whenever I eat spinach now. A little while after I eat a bag I start feeling better, but this improvement starts to wear off after several hours. Every day the highs seems to be getting shorter, and the lows seem to be getting longer. If I had to theorize, I’d say it’s starting to look more and more like I did indeed reverse my GPT overexpression into a GPT underexpression, as supplementing so much exogenous dolichol may have started to decrease my endogenous production. Again if this is the case, this could be a good thing. Slowly weening off of the spinach diet may cause my GPT to increase to a normal expression, and hopefully stay there permanently. This would be the final step in the spinach diet, and hopefully the cure for this imbalance.

I’m starting to ween off of the spinach diet by only eating 3/4ths of a bag a day for 4 days, then 1/2 a bag for another 4 days, then 1/4 a bag for 4 days, and finally 1/8 a bag for 4 days. I’ll try to keep my diet relatively healthy in the meantime, and I’ll keep you guys updated with any progress. Thanks again for all of your prayers.

#97

Unfortunately, I expected this moment. That’s why I didn’t express anything before now, even though I ate my spinach and got no result.

As soon as it started, this experience looked like Awor’s: Both of you discovered a new exciting theory, and everything fit incredibly well on paper, each one of those theories looked like the one, every new addition to the scientific puzzle appeared like absolutely no other theory could be truer than this one, and made the greatest sense. So, believing so strong in these new theories, both of you religiously tried with the greatest faith the according treatment, and it worked. There is a name for this experience: placebo effect.

I’m very sad to say that’s the only possible explanation, but of course, a placebo is not a cure, so, the effect has to disappear soon.

#98

What I don’t understand is, if there is some sort of hormonal or genetic (or whatever) issue, why would a placebo response even take place? As in, can our brains really override whatever was flipped around in our bodies? It is precisely because so many of us have temporary fixes from our own theories (this is a pattern I’m seeing all the time on here), that I do have to wonder how much of this mess is truly controlled by our mental state. Again, let me be clear that I don’t think we have thought our way into this mess or our minds are keeping us here, but there seems to be a real role that the mind is playing in keeping us down- its all just impossible to know and differentiate how/what though…

#99

I am not sure I would attribute TNTW’s recovery to the placebo effect. Spinach has magnesium in it and people have had amazing reactions to magnesium. That could have been what did it. Unfortunately the effects are only temporary.

#100

Again, jumping to conclusions at this point would be premature. The entirety of the cascade of effects caused by SRD5A3 inhibition has only recently begun to be revealed, and this has only been the first treatment to approach it from that angle. I should also make it clear that the “dolichol deprivation theory” is backed entirely by medical research, with a direct correlation between the actions of finasteride and the potential for subsequent glycosylation dysfunction. The “spinach diet” is just a theory based off of the dolichol deprivation theory. The spinach diet does not necessarily prove or disprove the dolichol deprivation theory.

Y-C - You were on Finasteride for 7 years and your body did not begin to experience side effects until later in your first year. I took finasteride for only 2 days and crashed almost immediately afterward, so we have a drastic difference between our body’s reaction to disruption. You cannot base a timeline of improvements based off of my own. Also how many consecutive days were you on the spinach diet, what kind of spinach were you eating, and how much were you eating?

As for the psychosomatic effects of the post finasteride syndrome, as well as the psychosomatic placebo effect of “creating a theory”, you should make your own topic about it. This topic is for the discussion of the effects and treatment of dolichol deprivation, not discrediting anecdotes based off of inferences.

nyer - While I don’t believe that PFS is psychosomatic in nature, we, like everybody else, can be greatly affected by our mental states. However I think it would be a fallacy to assume that all treatments based off of theories yield only psychosomatic results, even though it’s certainly possible that they can.

One reason why I don’t believe that my recovery was based off of the placebo effect is because this isn’t the first time I’ve tried a treatment like this. For example, I followed the juice diet for months with poor results, even though I had extremely optimistic hopes that it would work. I later followed a pomegranate juice diet after reading articles about how it boosts sexual function, and even though I convinced myself that it could work, it gave me absolutely no results. I took a battery of supplements hoping they could turn things around, and again, poor results. I tried maintaining a positive state of mind, I would fall into a negative state of mind, but none of it made any difference in regards to symptoms. I had become very pessimistic of all treatments, and very skeptical of all theories. The spinach diet has been the only treatment I’ve ever done that has made such a huge impact on me. Keep in mind that some of my symptoms that were reversed were lack of energy, weak emotions, chronic testicle pain, cold penis, darker yellow ejaculate, and lack of morning erections. That would have been one heck of a placebo.

joetz - I doubt it was the magnesium in spinach, as I’ve already been supplementing magnesium for over a year.

I’ve found several new research articles that are relevant to the function and inhibition of the glycosylation process, and the consequences of the Unfolded Protein Repsonse. I’ve been really busy with work lately and haven’t been able to research these things as much as I’d like, but I’ll try to make some time for it on Saturday. There’s an antibiotic called “tunicamycin” that is used in in-vitro cellular research, but is lethal to humans. It has a fascinating similarity to the actions of finasteride; it shuts down GPT, whereas finasteride only disrupts GPT, but both can invoke the UPR. There’s a myriad of research available for it, and I’ll let you guys know what I find.

For a quick update for how I’m doing, I’m actually feeling much better again! I think I may have been on the verge of an iron overload, which may have been starting to give me some adverse effects. This was really unexpected, as spinach contains oxalic acid which naturally inhibits iron absorption, and spinach only has non-heme iron, which is much less absorbable than heme-iron (the iron in meat). Also I’ve been taking supplements that are supposed to inhibit iron absorption anyway, such as calcium, magnesium, zinc, and oil of oregano. What I didn’t realize is that people can get iron overload from taking high quantities of Vitamin C along with their food (as I have been), which triples iron absorption, enhances non-heme iron absorption, and prevents iron loss. It was a strange predicament I was in for the past week, as every time I would eat my spinach I would feel better (because of the dolichol), but at the same time I would feel worse (because of the iron) in different areas. I’ve stopped taking my 500mg a day Vitamin C pills and I’ve been gradually feeling better.

The real test of whether or not this spinach treatment will have lasting effects on me should be revealed within the coming months after I completely ween off of it. If I was indeed successful in downexpressing my GPT, then it should hopefully allow the GPT to re-regulate itself. I don’t expect to be completely well after weening off (as re-regulation of the GPT may take time) but if it indeed worked, I should get better and stay better. I won’t know for sure until at least another month has passed, but things seem to be on the right track so far.